V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity.
Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3-21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens.
van Eeden, C; Wibmer, CK; Scheepers, C; Richardson, SI; Nonyane, M; Lambson, B; Mkhize, NN; Vijayakumar, B; Sheng, Z; Stanfield-Oakley, S; Bhiman, JN; Bekker, V; Hermanus, T; Mabvakure, B; Ismail, A; Moody, MA; Wiehe, K; Garrett, N; Karim, SA; Dirr, H; Fernandes, MA; Sayed, Y; Shapiro, L; Ferrari, G; Haynes, BF; Moore, PL; Morris, L
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